Palladium-Catalyzed Intermolecular C(sp3)-H Amidation
Palladium-Catalyzed Intermolecular C(sp3)-H Amidation
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DOI：
10.1002/anie.201108351
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Muniz, Kilian
中科院分区：
文献类型：
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作者：
Iglesias, Alvaro;Alvarez, Rosana;Muniz, Kilian
C1 H1 H键的直接胺化是一类重要的烷基化含氮化合物的独特合成方法。[1]在这种情况下，钯催化的分子间C（sp3）OH活化/烷基胺化是一个值得注意的未开发的过程。[2-4]另一方面，我们最近遇到了一个反应的基础上形成的烷基-氮键的s-烷基钯中间体的背景下，开发分子间二胺化反应的烯烃采用高氧化态钯催化。[5，6]我们在此报道了成功地将这种C3 CN键形成反应扩展到直接钯催化的氧化C33 H酰胺化反应。8-选择甲基喹啉（1a）作为模型底物，[7]并筛选了几种氧化剂，如二乙酸碘苯/双磺酰亚胺，[5a] PhI（OAc）NTs 2，[8]和N-氟双（苯磺酰基）-酰亚胺（NFSI）作为氮源。[5b在作为催化剂前体的乙酸钯（II）的存在下，用所有三种试剂容易地完成直接C2 H4活化/酰胺化反应（表1，条目1-3），并且观察到选择性产物形成;然而，产率高度依赖于反应条件。[11 1，4-二氧六环为最佳溶剂，且只有在高温下才能获得合适的反应速率。在不存在钯催化剂的情况下没有形成产物。最后，在用NFSI作为氧化剂的进一步催化剂筛选中，[Pd（hfacac）2]（hfacac=六氟乙酰丙酮化物）被确定为最佳催化剂源（表1，条目4-6）。通过化合物2b的X射线晶体结构分析明确地确定了新产物2的一般结构。[13]以前所未有的效率完成了8-甲基喹啉的许多另外的C2 OH酰胺化反应（方案1）。这些反应还包括2-叔丁基吡啶（3）的选择性单酰胺化反应，形成一个C3 N键。反应以原子经济的方式用市售催化剂[Pd（hfacac）2]和市售氧化剂NFSI进行，仅形成HF作为副产物。在酸性条件（HCl，75%）下容易地实现2b的脱保护，产生8-氨甲基喹啉，这允许方便地全面获得这类感兴趣的药物结构单元。[14]为了扩展底物范围，我们感兴趣的是一个更不稳定的配位基团，最近的概念由Yu等人。[15]为此，研究了2-甲基苯基醚5（表2）。[16][Pd（hfacac）2]和二氯化钯在这种情况下是完全无效的催化剂（表2，条目1和2），并且在广泛筛选后，发现Pd（OAc）2和浴铜灵（bc）的组合更合适（表2，条目3）。通过使用预先形成的浴铜灵钯络合物[（bc）Pd（0Ac）2][17]，
The direct amination of CĀH bonds is a unique synthetic approach towards the important class of alkylated nitrogen compounds.[1] In this context, the palladium-catalyzed intermolecular C (sp3) ĀH activation/amination of alkyl groups is a notably unexplored process.[2–4] On the other hand, we recently came across a reaction based on the formation of alkyl–nitrogen bonds from s-alkyl palladium intermediates in the context of developing intermolecular diamination reactions of alkenes employing high-oxidation-state palladium catalysis.[5, 6] We report herein on the successful extension of this CĀN bond-forming reaction to arrive at direct palladiumcatalyzed oxidative CĀH amidation reactions. 8-Methylquinoline (1a) was chosen as model substrate,[7] and several oxidants such as iodobenzene diacetate/bistosylimide,[5a] PhI (OAc) NTs2,[8] and N-fluorobis (phenylsulfonyl)-imide (NFSI) were screened as nitrogen sources.[5b, 9, 10] A direct CĀH activation/amidation reaction was readily accomplished with all three reagents in the presence of palladium (II) acetate as the catalyst precursor (Table 1, entries 1–3), and selective product formation was observed; however, yields were highly dependent on the reaction conditions.[11, 12] 1, 4-Dioxane was identified as the best solvent and a suitable rate was obtained only at high temperature. No product formed in the absence of palladium catalyst. Finally, in further catalyst screening with NFSI as the oxidant,[Pd (hfacac) 2](hfacac= hexafluoroacetylacetonate) was identified as the optimum catalyst source (Table 1, entries 4–6). The general structure of the new products 2 was unambiguously secured by X-ray crystal structure analysis of compound 2b.[13] A number of additional CĀH amidation reactions of 8-methylquinolines were accomplished with unprecedented efficiency (Scheme1). These also include the selective monoamidation of 2-tert-butylpyridine (3) with the formation of a single CĀN bond. The reaction proceeds with the commercially available catalyst [Pd (hfacac) 2] and commercial oxidant NFSI in an atom-economical manner, forming only HF as a by-product. Deprotection of 2b producing 8-aminomethylquinoline was readily achieved under acidic conditions (HCl, 75%), which allows for convenient overall access to this class of interesting pharmaceutical building blocks.[14] To extend the substrate scope, we were interested in a more labile coordinating group following a recent concept by Yu et al.[15] To this end, 2-methylphenyl ethers 5 were investigated (Table 2).[16][Pd (hfacac) 2] and palladium dichloride were completely inefficient catalysts in this case (Table 2, entries 1 and 2), and after extensive screening, a combination of Pd (OAc) 2 and bathocuproine (bc) was found to be more appropriate (Table 2, entry 3). By the use of the preformed bathocuproine palladium complex [(bc) Pd (OAc) 2][17] the